The application is for the continued support of a Program Project Grant in one of the NICHD-funded Mental Retardation Research Centers. The program comprises five projects whose goal is better understanding of the biochemical defects and/or pathogenesis of a number of inborn errors which can result in mental retardation and/or early death. Conditions to be studied are glutaric acidemia types I and II, homocystinuria due to cystathionine beta-synthase deficiency and various defects of the mitochondrial respiratory chain. Drs. Goodman, Frerman and Kraus, the three BF Stolinsky Laboratories investigators, have common interests and goals, interact on a daily basis, use the same methods and equipment, and utilize common tissue culture and recombinant DNA cores of the MRRC. Dr. Neil Howell, at the University of Texas in Galveston, has been collaborating with us for several years, and brings longstanding expertise and interest in the biochemistry and molecular biology of the respiratory chain to the project. Project I is concerned with glutaric acidemia, a disorder which causes mental retardation and degeneration of the basal ganglia, and will examine functional domains of normal glutaryl-coenzyme A dehydrogenase as well as how normal function is perturbed by naturally occurring mutations. Projects II and IV focus on the biochemistry and molecular biology of glutaric acidemia type II (GA2), a disorder which causes early death and (often) congenital anomalies, examining the effect of mutations of two proteins (ETF and ETF:QO) whose deficiency causes it. Project III seeks to identify mutations of the mitochondrial genome in patients with Leber's Hereditary Optic Neuropathy (LHON) and selected neuromuscular disorders; and project V will examine genetic heterogeneity in patients with propionic acidemia and homocystinuria due to deficiency of cystathionine beta-synthase. All of these projects have the common goal of eventually understanding how disturbed enzyme function leads to disease, since such information is essential for formulating rational approaches to therapy.